Id |
Subject |
Object |
Predicate |
Lexical cue |
T178 |
0-10 |
Sentence |
denotes |
DISCUSSION |
T179 |
11-260 |
Sentence |
denotes |
Chronic immunosuppressive therapy in patients with heart transplants is framed in a well-established protocol that includes calcineurin inhibitors possibly in combination with purine synthesis inhibitors or mammalian targets of rapamycin inhibitors. |
T180 |
261-411 |
Sentence |
denotes |
This therapeutic scheme is effective in deactivating the lymphocytes of the adaptive immune response, which is primarily involved in viral infections. |
T181 |
412-619 |
Sentence |
denotes |
Lacking any strong evidence regarding the treatment of patients with a heart transplant infected with SARS-CoV-2, we faced a new challenge in managing the viral infection in this immunosuppressed population. |
T182 |
620-815 |
Sentence |
denotes |
Strengthened by our experience with other viral infections in patients with heart transplants, especially cytomegalovirus, we followed the same management protocol in patients with COVID-19 [17]. |
T183 |
816-989 |
Sentence |
denotes |
Our first steps consisted of reducing immunosuppressive therapy in the patients with severe clinical forms of COVID-19, i.e. those with hypoxia who required hospitalization. |
T184 |
990-1072 |
Sentence |
denotes |
This strategy was adopted due to the lymphocytopenia characterizing this syndrome. |
T185 |
1073-1256 |
Sentence |
denotes |
For the milder form of the disease (i.e. the patient in self-quarantine at home), we opted not to reduce immunosuppression, instead implementing a close telephone monitoring protocol. |
T186 |
1257-1376 |
Sentence |
denotes |
Total suspension of immunosuppression has been proposed in some patients with kidney transplants and COVID-19 [18, 19]. |
T187 |
1377-1572 |
Sentence |
denotes |
However, we were concerned that suspending immunosuppression could lead to graft failure due to rebound activation of immunological memory, potentially exacerbated by the hyperinflammatory state. |
T188 |
1573-1870 |
Sentence |
denotes |
Furthermore, we do not yet know if the anti-inflammatory effect of chronic immunosuppressive therapy plays an undetermined role in the ‘cell damage cascade’ triggered by an uncontrolled cytokine storm and lymphocyte–macrophage activation, as has already been speculated in the literature [20, 21]. |
T189 |
1871-2041 |
Sentence |
denotes |
Indeed, some evidence suggests that lung damage in the severe forms of the disease is essentially due to immune hyperactivation rather than viral pathogenesis per se [6]. |
T190 |
2042-2189 |
Sentence |
denotes |
Conversely, we know that pharmacological interferences occurs between the antiviral drugs used to treat SARS-CoV-2 and calcineurin inhibitors [16]. |
T191 |
2190-2345 |
Sentence |
denotes |
The main issue of drug–drug interactions is an increased in immunosuppressant plasma concentrations due to their shared metabolism via cytochrome-P450-3A4. |
T192 |
2346-2506 |
Sentence |
denotes |
In particular, the interaction between lopinavir and calcineurin inhibitors has already been characterized as being based on suppression of cytochrome-P450-3A4. |
T193 |
2507-2604 |
Sentence |
denotes |
In contrast, the interaction between hydroxychloroquine and calcineurin inhibitors is less clear. |
T194 |
2605-2760 |
Sentence |
denotes |
Its metabolism via cytochrome-P450-3A4, as well as via cytochrome-P450-2C8, might theoretically increase the plasma concentration of the immunosuppressant. |
T195 |
2761-2833 |
Sentence |
denotes |
Consequently, close monitoring of immunosuppressant levels is warranted. |
T196 |
2834-2985 |
Sentence |
denotes |
Therefore, on one hand we chose to reduce chronic immunosuppressive therapy; on the other, we introduced corticosteroid therapy for 2 critical reasons. |
T197 |
2986-3089 |
Sentence |
denotes |
First, we tried to reduce the hyperinflammatory state and the overproduction of inflammation mediators. |
T198 |
3090-3230 |
Sentence |
denotes |
However, the use of corticosteroids in SARS-CoV-2 infection for treatment of acute respiratory distress syndrome remains controversial [22]. |
T199 |
3231-3460 |
Sentence |
denotes |
A retrospective analysis by Wang et al. in a Wuhan cohort showed that administration of early, low-dose and short-term corticosteroids was associated with faster improvement of clinical symptoms and absorption of lung focus [23]. |
T200 |
3461-3626 |
Sentence |
denotes |
Moreover, Siddiqi and Mehra [20] proposed the use of corticosteroids in immunosuppressed states when hypoxia is highlighted in moderate to severe clinical scenarios. |
T201 |
3627-3737 |
Sentence |
denotes |
In this regard, supportive therapy with hydroxychloroquine was also administered in all hospitalized patients. |
T202 |
3738-3992 |
Sentence |
denotes |
At the beginning of the COVID-19 pandemic, first reports and many national treatment guidelines suggested the use of hydroxychloroquine due to the anti-inflammatory and broad-spectrum antiviral effects observed with the severe acute respiratory syndrome. |
T203 |
3993-4135 |
Sentence |
denotes |
However, despite its common use, efficacy and safety were not confirmed by several dedicated observational studies and randomized trials [24]. |
T204 |
4136-4144 |
Sentence |
denotes |
The U.S. |
T205 |
4145-4241 |
Sentence |
denotes |
Food and Drug Administration subsequently revoked emergency use authorization for the drug [25]. |
T206 |
4242-4373 |
Sentence |
denotes |
On 17 June 2020, the World Health Organization announced that the hydroxychloroquine arm of the Solidarity Trial was being stopped. |
T207 |
4374-4571 |
Sentence |
denotes |
Data from major ongoing randomized clinical trials showed that hydroxychloroquine does not result in a reduction in mortality of hospitalized COVID-19 patients, when compared with standard of care. |
T208 |
4572-4656 |
Sentence |
denotes |
Only 2 of our 5 hospitalized patients were treated with ritonavir/lopinavir therapy. |
T209 |
4657-4836 |
Sentence |
denotes |
At the beginning of the Northern Italy pandemic, the Italian government agency for the regulation of drugs developed several protocols for off-label usage of antiretrovirals [26]. |
T210 |
4837-4981 |
Sentence |
denotes |
These 2 patients had fulfilled inclusion criteria for enrolment in one of the first randomized clinical trials for these drugs against COVID-19. |
T211 |
4982-5280 |
Sentence |
denotes |
With increasing evidence of both the absence of clinical benefit from ritonavir/lopinavir in the more seriously ill patients and the risk of toxicity associated with the combined administration of hydroxychloroquine and azithromycin, their usage in the general COVID-19 population has been limited. |
T212 |
5281-5357 |
Sentence |
denotes |
As a result, we have abandoned their use in our heart transplant population. |
T213 |
5358-5490 |
Sentence |
denotes |
Second, by introducing corticosteroids, we lowered the risk of graft failure due to the reduction in the dose of immunosuppressants. |
T214 |
5491-5623 |
Sentence |
denotes |
Nevertheless, given the debated effects of corticosteroids, the dose introduced was of medium proportion, as already suggested [23]. |
T215 |
5624-5817 |
Sentence |
denotes |
Therefore, we hypothesize that the broad-spectrum immunomodulatory effect of corticosteroids can help in the clinical management of transplant recipients affected with severe forms of COVID-19. |
T216 |
5818-6095 |
Sentence |
denotes |
Not least, we considered the administration of broad-spectrum antibiotic therapy to avoid superimposed bacterial infections that would have a detrimental effect on the prognosis due to immunosuppression and corticosteroids, and the reduction of defenses due to lymphocytopenia. |
T217 |
6096-6159 |
Sentence |
denotes |
We mainly opted for broad spectrum beta-lactams and macrolides. |
T218 |
6160-6309 |
Sentence |
denotes |
The patient who self-quarantined at home, despite presenting with similar onset symptoms, experienced a mild course of infection of shorter duration. |
T219 |
6310-6394 |
Sentence |
denotes |
The nasopharyngeal swab test was performed when the person was already asymptomatic. |
T220 |
6395-6489 |
Sentence |
denotes |
This patient was the only one on everolimus due to a high number of Epstein-Barr virus copies. |
T221 |
6490-6633 |
Sentence |
denotes |
Although there are speculations about this drug’s antiviral activity in relation to SARS-CoV-2, no conclusions can be drawn from a single case. |
T222 |
6634-6763 |
Sentence |
denotes |
Some authors claim a possible beneficial effect for everolimus as therapy for COVID-19 due to its immunomodulatory activity [27]. |
T223 |
6764-7058 |
Sentence |
denotes |
Moreover, the anti-replicative effect of controlling the spread of Epstein–Barr virus or cytomegalovirus can also be promising in SARS-CoV-2 infection on the basis of its ability to reduce mRNA translation, ribosome biogenesis, protein synthesis, mitochondrial metabolism and viral replication. |
T224 |
7059-7186 |
Sentence |
denotes |
Table 2 summarizes the available data on SARS-COV-2 infections in heart transplant recipients from reported case series [3–13]. |
T225 |
7187-7259 |
Sentence |
denotes |
When we analysed the overall data, the case-fatality-rate was about 20%. |
T226 |
7260-7350 |
Sentence |
denotes |
More than 80% of the patients were hospitalized, and half required intensive care support. |
T227 |
7351-7460 |
Sentence |
denotes |
The best immunosuppressive strategy is still being debated, in accordance with 60% of dosage reduction cases. |
T228 |
7461-7469 |
Sentence |
denotes |
Table 2: |
T229 |
7471-7552 |
Sentence |
denotes |
Summary of available data on SARS-COV-2 infections in heart transplant recipients |
T230 |
7553-7774 |
Sentence |
denotes |
Li et al. [3] Mathies et al. [5] Holzhauser et al. [6] Hsu et al. [7] Latif et al. [8] Hoek et al. [9] Kates et al. [10] Decker et al. [11] Fernandez- Ruiz et al. [12] Lee et al. [13] Caraffa et al Total, n (%) |
T231 |
7775-7831 |
Sentence |
denotes |
Number of patients 2 1 2 1 28 4 1 1 4 4 6 54 |
T232 |
7832-7856 |
Sentence |
denotes |
Baseline characteristics |
T233 |
7857-7985 |
Sentence |
denotes |
Age (years) 51; 43 77 59; 75 39 64 (53.3–70.5) 75; 65; 51; 50 74 62 64; 67; 63; 38 15; 25; 1.1; 2.4 67 (59–74) 59.1 |
T234 |
7986-8130 |
Sentence |
denotes |
Time from HTx (years) 16.2; 2.6 17 8; 20 3 8.6 (4.2–14.5) 21; 10; 10; 6 23 0.4 13.8; 10; 17.9; 8.7 0.4; 3; 0.5; 2 12 (4.0–17.5) 9.4 |
T235 |
8131-8186 |
Sentence |
denotes |
Male gender 2 1 1 1 22 3 1 1 4 1 5 42 (78) |
T236 |
8187-8254 |
Sentence |
denotes |
Arterial hypertension 0 1 2 1 20 NA NA 0 2 0 5 31 (63) |
T237 |
8255-8318 |
Sentence |
denotes |
Diabetes mellitus 0 1 2 1 17 NA NA 0 1 0 0 22 (45) |
T238 |
8319-8388 |
Sentence |
denotes |
Chronic kidney diseasea 0 1 2 0 10 NA NA 0 0 0 0 13 (27) |
T239 |
8389-8447 |
Sentence |
denotes |
Lung disease 0 0 0 1 10 NA NA 1 1 0 0 13 (27) |
T240 |
8448-8504 |
Sentence |
denotes |
PCI for CAV 0 1 0 0 NA NA NA 0 1 0 1 3 (14) |
T241 |
8505-8558 |
Sentence |
denotes |
BMI >30 0 0 0 1 NA NA NA 0 NA 0 1 2 (12) |
T242 |
8559-8582 |
Sentence |
denotes |
COVID-19 onset symptoms |
T243 |
8583-8633 |
Sentence |
denotes |
Fever 2 0 2 0 19 NA 1 1 4 3 6 38 (78) |
T244 |
8634-8688 |
Sentence |
denotes |
Chest pain 0 0 0 1 5 NA 0 0 0 1 NA 7 (16) |
T245 |
8689-8762 |
Sentence |
denotes |
Shortness of breath or cough 0 1 2 1 21 NA 1 1 4 2 6 39 (80) |
T246 |
8763-8833 |
Sentence |
denotes |
Gastrointestinal symptoms 1 0 2 0 11 NA 0 0 1 1 2 18 (37) |
T247 |
8834-8852 |
Sentence |
denotes |
Treatment regimens |
T248 |
8853-8883 |
Sentence |
denotes |
Maintenance immunosuppression |
T249 |
8884-8940 |
Sentence |
denotes |
Cyclosporine 0 0 1 0 5 1 0 1 3 2 6 19 (35) |
T250 |
8941-9008 |
Sentence |
denotes |
Mycophenolate mofetil 2 1 2 1 19 2 0 1 4 1 4 37 (69) |
T251 |
9009-9064 |
Sentence |
denotes |
Tacrolimus 2 0 1 1 22 3 1 0 1 1 0 32 (59) |
T252 |
9065-9142 |
Sentence |
denotes |
Proliferation sig- nal inhibitors 0 1 0 0 5 1 0 0 0 0 1 8 (15) |
T253 |
9143-9197 |
Sentence |
denotes |
Azathioprine 0 0 0 0 0 0 0 0 0 2 0 2 (4) |
T254 |
9198-9253 |
Sentence |
denotes |
Prednisone 0 0 0 1 19 2 0 1 4 2 0 29 (54) |
T255 |
9254-9293 |
Sentence |
denotes |
Number of immunosuppressive medications |
T256 |
9294-9336 |
Sentence |
denotes |
1 0 0 0 0 3 0 1 0 0 0 1 2 (8) |
T257 |
9337-9381 |
Sentence |
denotes |
2 2 1 2 0 8 3 0 0 0 1 5 14 (14) |
T258 |
9382-9426 |
Sentence |
denotes |
3 0 0 0 1 16 1 0 1 4 2 0 9 (35) |
T259 |
9427-9469 |
Sentence |
denotes |
4 0 0 0 0 1 0 0 0 0 0 0 0 (0) |
T260 |
9470-9488 |
Sentence |
denotes |
COVID-19 treatment |
T261 |
9489-9551 |
Sentence |
denotes |
Hydroxychloroquine 0 1 2 1 18 3 0 1 4 1 5 36 (67) |
T262 |
9552-9612 |
Sentence |
denotes |
Lopinavir/ritonavir 0 0 1 0 0 0 0 0 2 0 2 5 (9) |
T263 |
9613-9672 |
Sentence |
denotes |
Remdesivir/placebo 0 0 0 1 0 0 0 0 0 0 0 1 (2) |
T264 |
9673-9724 |
Sentence |
denotes |
Umifenovir 1 0 0 0 0 0 0 0 0 0 0 1 (2) |
T265 |
9725-9777 |
Sentence |
denotes |
Oseltamivir 0 0 1 0 0 0 0 0 0 0 0 1 (2) |
T266 |
9778-9828 |
Sentence |
denotes |
Ribavirin 1 0 0 0 0 0 0 0 0 0 0 1 (2) |
T267 |
9829-9875 |
Sentence |
denotes |
IFN-b 0 0 0 0 0 0 0 0 1 0 0 1 (2) |
T268 |
9876-9928 |
Sentence |
denotes |
Ganciclovir 2 1 0 0 0 0 0 0 0 0 0 3 (6) |
T269 |
9929-9982 |
Sentence |
denotes |
Tocilizumab 0 0 2 0 6 0 0 0 0 0 0 8 (15) |
T270 |
9983-10039 |
Sentence |
denotes |
Steroid bolus 1 0 1 0 8 0 0 1 0 1 5 17 (31) |
T271 |
10040-10085 |
Sentence |
denotes |
IVIG 1 0 1 0 0 0 0 0 0 0 0 2 (4) |
T272 |
10086-10112 |
Sentence |
denotes |
Immunosuppressant strategy |
T273 |
10113-10171 |
Sentence |
denotes |
Dose reduction 0 0 0 0 6 NA 0 0 0 1 5 12 (24) |
T274 |
10172-10238 |
Sentence |
denotes |
At least 1 withdrawal 1 1 2 1 16 NA 0 0 4 1 1 27 (55) |
T275 |
10239-10301 |
Sentence |
denotes |
Acute graft rejection 0 0 0 0 0 NA 0 0 0 0 0 0 (0) |
T276 |
10302-10316 |
Sentence |
denotes |
Major outcomes |
T277 |
10317-10374 |
Sentence |
denotes |
Hospitalized 2 1 2 1 22 NA 0 1 4 2 5 40 (82) |
T278 |
10375-10436 |
Sentence |
denotes |
Need for ICU stay 0 1 1 1 NA NA 0 0 2 0 2 7 (33) |
T279 |
10437-10501 |
Sentence |
denotes |
Invasive ventilation 0 0 1 0 NA NA 0 0 2 0 1 4 (19) |
T280 |
10502-10570 |
Sentence |
denotes |
Self quarantined at home 0 0 0 0 6 NA 1 0 0 2 1 10 (20) |
T281 |
10571-10619 |
Sentence |
denotes |
Death 0 0 0 0 7 1 0 0 1 0 2 11 (20) |
T282 |
10620-10675 |
Sentence |
denotes |
Discharged 2 1 1 1 11 NA 0 0 2 2 3 23 (47) |
T283 |
10676-10740 |
Sentence |
denotes |
Remained hospitalized 0 0 1 0 4 NA 0 1 1 0 0 7 (14) |
T284 |
10741-11027 |
Sentence |
denotes |
BMI: body mass index; CAV: cardiac allograft vasculopathy; HTx: heart transplant; IFN-b: interferon-beta; ICU: intensive care unit; IVIG: intravenous gamma globulin; NA: not available; PCI: percutaneous coronary intervention; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. |
T285 |
11028-11116 |
Sentence |
denotes |
a Defined by a glomerular filtration rate ˂30 ml/min and the presence of haemodialysis. |
T286 |
11117-11194 |
Sentence |
denotes |
The mortality rate remains higher compared to that of the overall population. |
T287 |
11195-11295 |
Sentence |
denotes |
It is still unclear whether any of the adopted approaches actually influence prognosis and survival. |
T288 |
11296-11452 |
Sentence |
denotes |
Our adopted therapeutic strategy resulted in one-third mortality in this particular population at risk of severe illness from infection with the SARS-CoV-2. |
T289 |
11453-11600 |
Sentence |
denotes |
One patient of advanced age with an already documented cardiac allograft vasculopathy did not overcome the disease, having developed a severe form. |
T290 |
11601-11738 |
Sentence |
denotes |
Available data show a higher mortality rate among older male patients with cardiovascular comorbidities who are infected with SARS-CoV-2. |
T291 |
11739-11910 |
Sentence |
denotes |
Furthermore, we must consider that during the outbreak the maximum standard of care was not achievable for all due to the limited availability of intensive care unit beds. |
T292 |
11911-12062 |
Sentence |
denotes |
The other death was the consequence of a complicated course of hospitalization for a patient not responsive to antibiotic therapy who developed sepsis. |
T293 |
12063-12215 |
Sentence |
denotes |
In addition, in 1 case we even managed to treat the infection at home in an unprecedented era in which healthcare resources are limited by the pandemic. |
T294 |
12216-12383 |
Sentence |
denotes |
Apart from a bacterial superinfection and progression of respiratory disease, the only major complication that occurred during hospitalization was an ischaemic stroke. |
T295 |
12384-12588 |
Sentence |
denotes |
Anecdotal cases regarding neurological events in patients with COVID-19 have been reported in the literature to date [28] and evidenced shows a hypercoagulability state in patients with severe forms [29]. |
T296 |
12589-12680 |
Sentence |
denotes |
Further investigations are needed to understand the aetiopathogenesis of this complication. |
T297 |
12682-12693 |
Sentence |
denotes |
Limitations |
T298 |
12694-12797 |
Sentence |
denotes |
The major limitations regarding our experience are related to the small size of the population studied. |
T299 |
12798-12947 |
Sentence |
denotes |
Months after the beginning of the pandemic, mounting evidence is emerging for therapy and supportive care practices for managing COVID-19 infections. |
T300 |
12948-13082 |
Sentence |
denotes |
More studies are needed to evaluate and correlate clinical and laboratory data to support our immunosuppressive modification strategy. |
T301 |
13083-13250 |
Sentence |
denotes |
The cohort of heart transplant recipients makes up a minimal part of the affected population and the need to collect patients in a multicentre study remains essential. |